Prediction of the conformational requirements for binding to the kappa-opioid receptor and its subtypes. I. Novel alpha-helical cyclic peptides and their role in receptor selectivity.

A conformational search of two similar kappa-selective cyclic Dynorphin A (Dyn A) analogues is presented. [Cys5, Cys11] Dyn A1-11-NH2 (1) and [Cys5, D-Ala8, Cys11] Dyn A1-11-NH2 (2) are not only highly potent kappa-selective peptides but they also exhibit exceptional selectivity for kappa receptors in the central (brain) vs. the peripheral (ileum) systems. Molecular mechanics systematic searching of the conformational preferences of the cyclic moieties of 1 and 2 produced 741 and 1003 starting ring structures, which were minimized at two dielectric constants of 2.0 and 80.0 in the AMBER force field. By rms superimposition, these low energy structures were grouped into conformational families for each ring system minimized at each dielectric. Comparison of the lowest energy structure of each of these families demonstrated that two (labeled A and B) were found as low energy ring systems for both 1 and 2 after minimization at either dielectric constant. These two structures are thus predicted to be the putative binding conformations for Dynorphin A at receptors in the brain. Interestingly, one of these putative binding structures exhibited an alpha-helical conformation in the disulfide bridged ring that has not been observed for small cyclic peptides of this nature before. Molecular dynamics simulation of the helical binding structures indicated that the helical configuration in 2 is lower in energy and is more conformationally stable than that of 1. We correlate this with the increased selectivity and potency of 2 for kappa receptors in the brain compared to the periphery, implying that this may be due to an alpha-helical conformation in the cyclized address or helical induction in the message sequence.